Role of Silicosis in Silica-associated Lung Cancer

Role of Silicosis in Silica-associated Lung Cancer Background Crystalline silica is a mineral compound composed of silicon and oxygen atoms that are arranged in a repeating pattern. Common polymorphs of crystalline silica include quartz, cristobalite and tridymite, with quartz as the most common form. Human exposure to crystalline silica is most often from occupational tasks that involve disturbance, use or manufacture of quartz-containing materials, including stonecutting, mining, quarrying and ceramics.[i],[ii] In 1997, the International Agency for Research on Cancer (IARC) concluded there was sufficient evidence for carcinogenicity in humans with occupational exposure to respirable crystalline silica in the quartz or cristobalite form.[iii] The 1997 IARC Monograph noted the greater part of epidemiologic studies reported the presence of silicosis (referring to the chronic or also known as classic type), a fibrotic disease of the lung that is associated with high exposure to respirable crystalline silica dust, increases excess lung cancer risk among workers exposed to silica. However, it remains unclear whether lung cancer development among these workers is due to the presence of silicosis or due to exposure to significant silica levels with silicosis being a confounder rather than a prerequisite. A recent literature review of relevant epidemiological studies confirmed that there remains uncertainty about excess lung cancer risk exclusively among silicotic workers due to the shortcomings of the design of existing epidemiological studies, including the inaccurate measurement of silica exposure, inadequate characterization of the exposure-response relationship between crystalline silica and lung cancer, inadequate control for potential confounders such as known lung cancer risk factors and the presence of other carcinogenic agents in the workplace, and the absence of comparing the lung cancer risk between silicotics and non-silicotic (do not have silicosis) workers as controls. The proposed research study attempts to clari fy the role of silicosis in silica-associated lung cancer development by addressing some of the identified study design challenges. Significance Determining if silicosis is a prerequisite for lung cancer development has important public health implications for setting occupational standard for silica exposure, implementing workplace medical surveillance programs and determining causation in medico-legal cases. For example, if it is determined that lung cancer risk increases among workers exposed to silica only in the presence of silicosis, then efforts should be focused on reducing high silica exposure to a level that reduces the risk of developing silicosis. However, if it is determined that silicosis is not a prerequisite, then lung cancer development can occur at silica exposures lower than those likely to cause silicosis, which makes prevention of exposure to high silica levels not adequate for worker protection. Specific Aims To better understand the role of silicosis in the pathway leading to lung cancer from occupational exposure to silica, the specific aims of the study are: To examine the association between occupational exposure to crystalline silica and lung cancer risk in the presence and absence of silicosis and To measure the exposure-response relationship between crystalline silica and lung cancer risk with risk estimates adjusted by silicosis Procedures/Methods Study Design and Population A nested case-control study design will be utilized to analyze the association between occupational exposure to crystalline silica and lung cancer risk among silicotic and non-silicotic workers from an original cohort mortality study. The original study was conducted among workers from the Vermont granite industry.[iv] They were identified from a group insurance program enrollment between January 1st, 1947 and December 31st, 1998, Vermont Department of Health Division of Industrial Hygiene (DIH) records, pension records, data from a study of workers employed from 1979 to 1987 and data from a study of retired workers.iv The data from the multiple sources were linked to avoid duplications. As a result, the cohort consisted of 7052 Vermont granite industry workers. The mortality follow-up of the cohort identified 359 observed lung cancer deaths. iv Age at death, smoking history and silica dust exposure, medical history of obstructive lung disease and demographics will be compared betwee n the cases and controls. Workers that did not have sufficient smoking information, work histories and available chest radiographs were excluded. The exposure of interest will be the cumulative exposure to silica dust. The study population is unique in that the Vermont granite industry has a long history of silica exposure, medical surveillance and a general exclusion of occupational exposures associated with lung cancer. Case Ascertainment Lung cancer cases will be ascertained from the original Vermont granite industry cohort study. The vital status and cause of data was ascertained from the US National Death Index (NDI), US Social Security Administration vital status records and the Vermont State Records Office. The cause of death was coded to the 9th Revision of the International Classification of Diseases (ICD-9). Control Ascertainment Controls will also be ascertained from the original cohort study. The controls are defined as workers who did not die from lung cancer. Lung cancer cases will be matched to 2 controls by age. Silicosis Ascertainment The presence of silicosis among the cases and controls would be obtained from compensation and medical surveillance records. Silica Exposure Measurement Cumulative exposure to respirable crystalline silica was measured using a job exposure matrix that utilized industrial hygiene measurements. The cumulative exposures are categorized in quartiles. Sample Size Justification According to the sample size calculator (http://www.surveysystem.com/sscalc.htm), it is estimated that this study would need approximately 360 subjects are required in the study to obtain the confidence level of 95% with an interval of 5%, if we are selecting subjects from the 7052 Vermont granite industry workers cohort. We will strive to obtain 90 cases and 180 controls, based on the availability of sufficient smoking information, work histories and chest radiographs. Statistical Analysis Statistical analysis will be performed to calculate odds ratios to examine the association between lung cancer and total and each quartile of cumulative silica exposure in the presence and absence of silicosis. Odds ratios will be adjusted for smoking, obstructive lung disease and age as they are potential confounders. Odds ratios will be calculated with 95% confidence intervals. Study Strengths Strengths of the proposed study include: comparing the association of silica exposure and lung cancer in both silicotic and non-silicotic workers measuring the exposure-response relationship between silica and lung cancer risk, taking into account the presence and absence silicosis controlling for potential confounders of smoking and obstructive lung disease excluding potential confounders of other occupational exposures associated with lung cancer by studying the granite industry cohort conducting a nested case-control study is less expensive than a full cohort study since a comparably significant number of lung cancer cases have emerged Study Limitations Potential biases and study limitations are: Selection bias is a concern as silicotic workers are identified from compensation and medical surveillance records Silicotic workers may be diagnosed by different criteria, but resulting in non-differential misclassification Differential misclassification may result from categorizing the silica exposure in quartiles Silica exposure assessment may not be accurate if the job exposure matrix is methodologically sound Only studied one type of industry associated with silica exposure Non-diseased persons from whom the controls are selected may not be fully representative of the original cohort due to loss to follow-up or death References [i] International Labour Organization (ILO)/SafeWork Bookshelf (2006). ILO Encyclopaedia of Occupational Health and Safety: Volume 1, Part I. Body: Chapter 10 Silicosis. Available at http://www.ilo.org/safework_bookshelf/english?dnd=170000102nh=0. [ii] Occupational Safety and Health Administration (OSHA) (2002). OSHA Fact Sheet: Crystalline Silica Exposure Health Hazard Information [Electronic Version]. Available at http://www.osha.gov/OshDoc/data_General_Facts/crystalline-factsheet.pdf [iii] WHO/IARC (1997). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Silica, Some Silicates, Coal Dust and para-Aramid Fibrils [Electronic Version]. Volume 68; available at http://monographs.iarc.fr/ENG/Monographs/vol68/mono68.pdf. [iv] Vacek PM, Verma DK, Graham WG, Callas PW, Gibbs GW (2010). Mortality in Vermont granite workers and its association with silica exposure. Occup Environ Med, 68(5), 312-318.